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Chemokine (C-C motif) ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine (because it has six conserved cysteine residues instead of the four cysteines typical to chemokines), exodus-2, and secondary lymphoid-tissue chemokine (SLC).[5][6][7] CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7.[8] The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.[9]
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The gene for CCL21 is located on human chromosome 9.[10] CCL21 is classified as a homeostatic chemokine, it is produced constitutively. However, its expression increases during inflammation.[9][11]
Chemokine CCL21 contains an extended C-terminus which is not found in CCL19, another ligand of CCR7. C-terminal tail is composed of 37 amino acids rich in positively charged residues and therefore, it has high affinity for negatively charged molecules of the extracellular matrix. The cleavage of the C-terminal tail by peptidases produces a soluble form of CCL21.[12] The soluble CCL21 occurs also in physiological conditions. It does not bind to extracellular matrix and therefore, its function differs from the function of the full-length CCL21.[11]
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Migration to secondary lymphoid organs
Naïve T cells circulate through secondary lymphoid organs until they encounter the antigen.[13] CCL21 is a chemokine involved in the recruitment of T cells into secondary lymphoid organs. It is produced by lymphatic endothelial cells and lymph node stromal cells.[7][12] Full-length CCL21 is bound to glycosaminoglycans, and endothelial cells and it induces the chemotactic migration of T cells and the cell adhesion caused by integrin activation.[9] In contrast, the soluble CCL21 is not involved in the induction of the cell adhesion.[11] After T cells enter the lymph nodes through high endothelial venules, they are attracted to the T cell zone, where fibroblastic reticular cells are the abundant source of CCL21.[13][9]
CCL21/CCR7 interaction also plays a role in the migration of dendritic cells to the secondary lymphoid organs.[14][11][9] Dendritic cells upregulate the expression of CCR7 during their maturation.[14] CCL21 is bound to the lymphatic vessels and attracts CCR7 expressing dendritic cells from peripheral tissues. Then they migrate along the chemokine gradient to the lymph node where they present the antigen to T cells.[9] Interactions between dendritic cells and T cells are necessary for the initiation of the adaptive immune response.[15] When CCL21 is not recognized by the cells (for example in CCR7-deficient mice), a delayed and reduced adaptive immune response occurs due to reduced interactions between dendritic cells and T cells in the lymph nodes.[9] Semi-mature dendritic cells express CCR7 in the absence of a danger signal. They use CCL21 chemokine gradient for the migration to the lymph nodes even when there is no inflammation in the body, and they contribute to peripheral tolerance.[11]
Other cells using chemokine CCL21 for the migration to the lymph nodes are B cells. However, they are less dependent on it in comparison to T cells.[9]
T cell development in the thymus
CCL21/CCR7 interaction plays a role in the T cell development in the thymus. CCL21 is produced in the thymus medulla by medullary thymic epithelial cells, and it attracts single positive thymocytes from the thymus cortex to the medulla, where they undergo negative selection to delete autoreactive thymocytes.[9]
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